Ruegenberg, Sabine, Horn, Moritz ORCID: 0000-0002-5324-7256, Pichlo, Christian ORCID: 0000-0002-3156-5667, Allmeroth, Kira, Baumann, Ulrich and Denzel, Martin S. (2020). Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis. Nat. Commun., 11 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

Full text not available from this repository.

Abstract

Glutamine fructose-6-phosphate amidotransferase (GFAT) is the key enzyme in the hexosamine pathway (HP) that produces uridine 5-diphospho-N-acetyl-d-glucosamine (UDP-GlcNAc), linking energy metabolism with posttranslational protein glycosylation. In Caenorhabditis elegans, we previously identified gfat-1 gain-of-function mutations that elevate UDP-GlcNAc levels, improve protein homeostasis, and extend lifespan. GFAT is highly conserved, but the gain-of-function mechanism and its relevance in mammalian cells remained unclear. Here, we present the full-length crystal structure of human GFAT-1 in complex with various ligands and with important mutations. UDP-GlcNAc directly interacts with GFAT-1, inhibiting catalytic activity. The longevity-associated G451E variant shows drastically reduced sensitivity to UDP-GlcNAc inhibition in enzyme activity assays. Our structural and functional data point to a critical role of the interdomain linker in UDP-GlcNAc inhibition. In mammalian cells, the G451E variant potently activates the HP. Therefore, GFAT-1 gain-of-function through loss of feedback inhibition constitutes a potential target for the treatment of age-related proteinopathies. p id=Par Mutations in the hexosamine pathway key enzyme glutamine fructose-6-phosphate amidotransferase (GFAT-1) improve protein quality control and extend C. elegans lifespan. Here the authors present the crystal structures of full-length human GFAT-1 alone and with bound ligands and perform activity assays, which show that gain-of-function in the longevity-associated G451E variant is caused by a loss of feedback regulation.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ruegenberg, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horn, MoritzUNSPECIFIEDorcid.org/0000-0002-5324-7256UNSPECIFIED
Pichlo, ChristianUNSPECIFIEDorcid.org/0000-0002-3156-5667UNSPECIFIED
Allmeroth, KiraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumann, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Denzel, Martin S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-345452
DOI: 10.1038/s41467-020-14524-5
Journal or Publication Title: Nat. Commun.
Volume: 11
Number: 1
Date: 2020
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HUMAN GLUTAMINE-FRUCTOSE-6-PHOSPHATE AMIDOTRANSFERASE; FRUCTOSE 6-PHOSPHATE AMIDOTRANSFERASE; ANGSTROM CRYSTAL-STRUCTURE; GLUCOSAMINE-6-PHOSPHATE SYNTHASE; O-GLCNACYLATION; L-GLUTAMINE; PHOSPHORYLATION; IDENTIFICATION; PURIFICATION; DOMAINSMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34545

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item